The leading commercial goal of our company is to develop novel therapeutics to inhibit the human oncogene, c-Myc. C-Myc is a major human oncogene that is estimated to contribute to at least 70% of all human cancers, most of which are aggressive and respond poorly to current therapies. Despite more than 30 years of research, the development of drugs that inhibit c-Myc has been unsuccessful because the protein is a transcription factor that lacks pockets for small molecules to bind. Therefore, developing novel treatments that inhibit c-Myc is considered one of the most important goals for advancing cancer therapeutics. Recently studies from several laboratories including ours have shown that the small ubiquitin-like modifications (SUMO) are critical for c-Myc-dependent tumorigenesis. Our initial studies are focused on colorectal cancers, because these cancers are almost 100% dependent on c-Myc and new therapies are critically needed for metastatic colorectal cancers to improve patient survival. SUMOylation is important for c-Myc expression through activation of beta-catenin/Tcf-4, the transcription factor for c-Myc expression in colorectal cancers. In preliminary studies, we have identified a very specific and potent inhibitor scaffold of SAE, the activating enzyme that catalyzes SUMO modifications, using high throughput screening. Inhibition of SUMOylation with this inhibitor or by knockdown of SAE dramatically reduced c-Myc level in colorectal cancer cells. We have designed strategies to improve the potency of the lead compound based on our recent discovery of its novel mechanism of action, which indicates a tractable approach to increase its specificity, potency and duration of action. We will then determine the specificity and cellular mechanisms of the improved compounds and will conduct toxicity and efficacy studies in animal models. Our results will significantly advance the field by providing the first proof-of-concept in animal models that SUMOylation is a potential target to inhibit the c-Myc oncogene.